This application claims the priority from and the benefit of Korean Patent Application No. 10-2015-0043602 filed on Mar. 27, 2015, which is hereby incorporated in its entirety by reference as if fully set forth herein.
Inflammation is the expression of a normal and protective in vivo defense mechanism that locally occurs against tissue damages caused by physical trauma, harmful chemicals, infection by microorganisms, or irritant substances among in vivo metabolites. Such inflammation is triggered by various chemical factors produced from damaged tissues and migrating cells, while these chemical factors are known to vary according to the type of inflammation process. In normal cases, the living body neutralizes or removes pathogenic factors and regenerates damaged tissues through inflammatory responses, thereby restoring normal structures and functions, but if not, the living body may progress into a diseased state, such as chronic inflammation. In addition, in cases where inflammation is improperly triggered by harmless substances (such as pollens) or autoimmune responses (such as asthma and rheumatoid arthritis), defense responses per se damage tissues, and therefore, agents for preventing or treating inflammatory diseases are needed. Inflammatory responses can be observed in almost all clinical diseases, some of which are bacterial diseases being able to be treated by causative therapy through administration of antibiotics, while most of inflammatory diseases are known as incurable diseases having no specific treatments since such inflammatory diseases are caused by tissue damage due to autoimmune responses.
The most typical agents for preventing or treating such inflammatory diseases are largely classified into steroidal and non-steroidal agents, respectively. Among these agents, most of synthetic agents for preventing or treating inflammatory diseases have many side effects, besides their main functions. That is, in order to treat inflammatory diseases, nonsteroidal anti-inflammatory drugs (NSAIDs) are used to alleviate the inflammation; steroids are used in cases of severe inflammation or no efficacy of NSAIDs; and immunosuppressive drugs or surgery is employed in cases of intractable inflammation. Here, the NSAIDs mainly inhibit cyclooxygenase (COX) to suppress the production of prostaglandins involved in inflammatory responses, and thereby exhibiting actions of preventing or treating inflammatory diseases. However, they cause side effects (such as gastrointestinal disorders, hepatic disorders, kidney dysfunctions, and the like), and thus the long-term use of NSAIDs is difficult.
Meanwhile, allergies are systemic or local disorders of the living body based on immune responses which are the aggregation of a wide range of complex pathological phenomena. Allergies in the human body are classified into Types I, II, III, and IV according to their immune mechanisms, respectively. Among these, Type I allergies, which are involved in an immediate hypersensitivity reaction, account for an important part in the clinical practice, and include atopic dermatitis, allergic rhinitis, bronchial asthma, hay fever, and pollinosis.
It was discovered in 1953 that Type I allergies occur by the activation of mast cells, and granules of such mast cells contain a large quantity of histamine, which is a mediator of inflammatory responses. The release of histamine from mast cells in allergic responses was discovered. While the mechanisms for these phenomena were being researched, immunoglobulin E (IgE) was discovered by Ishizaka, and such discovery served as an important factor to reveal that mast cells are involved in immediate allergic responses. That is, the high-affinity IgE receptors are present on the surface of mast cells, while IgE binds to such receptors and then antigens again binds thereto, thereby forming cross-linkage, causing a degranulation reaction, so that the contents in granules, that is, synthesized and stored preformed mediators, such as histamine, serotonin, and bradykinin, and protease, proteoglycan, and the like are simultaneously released (Ishizaka, Hosp Pract.; 12(1):57-67, 1977).
Type I allergies may be summarized as a natural phenomenon of the living body, which is caused by active amines and proteases, which are granular contents released by the activation of mast cells, lipid mediators produced from cell membrane phospholipids, and cytokines, such as IL-3 (mast cell proliferation factor), IL-4, and IL-5, which are well known as modulators of immune responses (Galli S J et al., Curr Opin Immunol.; 3(6):865-872, 1991; Bradding P et al., J Immunol.; 151(7):3853-3865, 1993).
In addition, when the skin is exposed to an allergic antigen, antigen-specific IgE binds to an IgE receptor on the surface of Langerhans cells, and is transferred to T cells on the surface of the antigen, thereby activating the T cell. Unlike normal state, in allergic skin diseases, especially atopic dermatitis, Th2 is activated to release cytokines, such as IL-4, IL-5, IL-6, IL-8, IL-10 and IL-13, thereby promoting the production of IgE in B cells and promoting the degranulation of activated mast cells, so that cytokines and histamine are released (Baruah C. C. et al., Pharmacol Res.; 38(6):487-92, 1998; Karadag C. H. et al., Braz J Med Biol Res.; 33(3):327-330, 2000; Paolini R. et al., Nature.; 353(6347):855-858, 1991).
Currently, allergy drugs that are clinically used may be broadly classified into a degranulation inhibitor, a chemical transmitter action inhibitor, a chemical transmitter synthesis inhibitor, and the like, according to their action mechanism. Among these drugs, the chemical transmitter action inhibitor and the chemical transmitter synthesis inhibitor have a relatively clear site of drug action, whereas the degranulation inhibitor has an unclear action mechanism, and these drugs may incur several side effects due to their long-term administration. Therefore, for treatment of Type I allergies, it may be very important to elucidate action mechanisms of the production and release of these physiologically active substances in mast cells and to minimize side effects due to their long-term use.